American Regent announces an FDA-Approved Pediatric Indication Exclusivity for Venofer (Iron Sucrose Injection, USP)

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1 One Luitpold Drive, PO Box 91, Shirley, New York (631) (8) Fax (631) FOR IMMEDIATE RELEASE October 19, 212 Contact: American Regent, Inc. Walter Tozzi, R.Ph., M.S., M.B.A. VP of Marketing and Professional Services American Regent announces an FDA-Approved Pediatric Indication Exclusivity for (Iron Sucrose Injection, USP) Shirley, NY (October 19, 212): American Regent, Inc. is pleased to announce that (iron sucrose injection, USP) was granted 3 year exclusivity by FDA for the treatment of Iron Deficiency Anemia in pediatric patients., the #1 IV iron in the United States, is the only IV iron approved for adults and children ages 2 years and older for IDA in all stages of Chronic Kidney Disease (CKD). Iron Deficiency Anemia (IDA) is a common co-morbid condition in pre-dialysis CKD and dialysis patients where the body does not have enough iron to produce a normal supply of red blood cells. The prevalence of End Stage Renal Disease (ESRD) in pediatric patients has grown 32 since According to the United States Renal Data Systems (USRDS) 212 Annual Report, the prevalence rate of pediatric ESRD in the United States reached 86 per 1 million population in 21, with almost 7, pediatric patients on dialysis. Also, children appear to receive less intravenous anemia treatment than adults, with more than 85 of adult patients receiving IV iron, compared to 61 of children. 2 will have 3 year exclusivity for the Pediatric indication through September 21, 215. We are pleased to the FDA has granted Pediatric Exclusivity. This is another important and strategic step for American Regent, as we continue to build and grow our IV Iron franchise. said Mary Jane Helenek, President and CEO of Luitpold Pharmaceuticals. 1 of 3 VEN11912 Iss. 1/212

2 (iron sucrose injection, USP) is approved in pediatric patients (2 years of age and older) for maintenance treatment at a dose of.5 mg/kg, not to exceed 1 mg per dose, every two weeks (for hemodialysis patients) and every four weeks (for non-dialysis and peritoneal-dialysis patients) for a period of 12 weeks. may be administered undiluted by slow intravenous injection over 5 minutes or diluted in 25 ml of.9 NaCl and administered over 5 to 6 minutes. treatment may be repeated if necessary. The dosing for iron replacement treatment in pediatric patients has not been established. Headquartered in Shirley, NY, American Regent, Inc., distributes over 8 pharmaceutical products under the PharmaForce or their own label, including (iron sucrose injection, USP) which has been the #1 selling IV iron therapy in the U.S. since 23. For more information about this product or other American Regent or PharmaForce products, please contact our customer service department at Fresenius Medical Care- North America, under an exclusive sublicense from American Regent, will continue to promote and distribute to Stage V Hemodialysis and Peritoneal Dialysis Dependent-CKD patients in Free Standing Outpatient Dialysis Facilities. (iron sucrose injection, USP) is manufactured under license from Vifor (International) Inc., Switzerland. 1 Warady, BA., Chadha, V. Chronic kidney disease in children: the global perspective. Pediatr Nephrol. 27 December; 22(12): USRDS 212 Annual Data Report, National Institute of Health Source: American Regent, Inc. See accompanying Important Safety Information and Full Prescribing Information 2 of 3 VEN11912 Iss. 1/212

3 VENOFER (IRON SUCROSE INJECTION, USP) IMPORTANT SAFETY INFORMATION Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving (iron sucrose injection, USP). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop immediately. Monitor patients for signs and symptoms of hypersensitivity during and after administration for at least 3 minutes and until clinically stable following completion of the infusion. Only administer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of. Hypotension following administration of may be related to rate of administration and total dose delivered. is contraindicated in patients with known hypersensitivity to. Do not administer to patients with evidence of iron overload. In efficacy studies in non-dialysis dependent-ckd patients (N=139), the most frequent adverse events ( 5) whether or not related to administration, were nausea (8.6), taste disturbance (7.9), peripheral edema (7.2), diarrhea (7.2), dizziness (6.5), hypertension (6.5), infusion site pain or burning (5.8), dyspnea (5.8), and vomiting (5.). In multi-dose efficacy studies in hemodialysis dependent-ckd patients (N=231), the most frequent adverse events (> 5) whether or not related to administration, were hypotension (39.4), muscle cramps (29.4), nausea (14.7), headache (12.6), graft complications (9.5), vomiting (9.1), dizziness (6.5), hypertension (6.5), chest pain (6.1), pain in extremity (5.6), and diarrhea (5.2). In the study of peritoneal dialysis dependent-ckd patients (N=75), the most frequent adverse events, whether or not related to administration, reported by 5 of these patients, were infections and infestations (nasopharyngitis, sinusitis, upper respiratory tract, pharyngitis) (16.), diarrhea (8.), vomiting (8.), hypertension (8.), peripheral edema (5.3), and nausea (5.3). In a randomized open-label dose ranging trial of iron maintenance treatment in pediatric patients with CKD on stable erythropoietin therapy, 57 of the treated patients (27/47) receiving.5 mg/kg experienced a treatment-emergent adverse reaction, 11 of which were serious. The most common treatment-emergent adverse reactions (> 2 of patients) in all patients were headache (6), respiratory tract viral infection (4), peritonitis (4), vomiting (4), pyrexia (4), dizziness (4), cough (4), renal transplant (4), nausea (3), arteriovenous fistula thrombosis (2), hypotension (2), and hypertension (2.1). 3 of 3 VEN11912 Iss. 1/212

4 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VENOFER safely and effectively. See full prescribing information for VENOFER. (iron sucrose injection, USP) Initial U.S. Approval: RECENT MAJOR CHANGES Indications and Usage (1) 9/212 Dosage and Administration (2.4, 2.5) 9/ INDICATIONS AND USAGE is an iron replacement product indicated for the treatment of iron deficiency anemia in patients with chronic kidney disease (CKD). (1) DOSAGE AND ADMINISTRATION Population Dose Adult patients Pediatric patients Hemodialysis Dependent- Chronic Kidney Disease (HDD-CKD) (2.1) Non-Dialysis Dependent- Chronic Kidney Disease (NDD-CKD) () Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3) HDD-CKD (2.4), PDD- CKD or NDD-CKD (2.5) 1 mg slow intravenous injection or infusion 2 mg slow intravenous injection or infusion 3 mg or 4 mg intravenous infusion.5 mg/kg slow intravenous injection or infusion DOSAGE FORMS AND STRENGTHS ml single-use vial / 2 mg elemental iron (2 mg/ml) (3) 5 ml single-use vial / 1 mg elemental iron (2 mg/ml) (3) 2.5 ml single-use vial / 5 mg elemental iron (2 mg/ml) (3) CONTRAINDICATIONS Known hypersensitivity to (4) WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after administration for at least 3 minutes and until clinically stable following completion of each administration. Only administer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1) Hypotension: may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of. (5.2) Iron Overload: Regularly monitor hematologic responses during therapy. Do not administer to patients with iron overload. (5.3) ADVERSE REACTIONS The most common adverse reactions ( 2) following the administration of are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at or FDA at 1-8-FDA-188 or See 17 for PATIENT COUNSELING INFORMATION Revised: 9/212 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) 2.3 Adult Patients with Peritoneal Dialysis Dependent- Chronic Kidney Disease (PDD-CKD) 2.4 Pediatric Patients (2 years of age and older) with HDD- CKD for iron maintenance treatment 2.5 Pediatric Patients (2 years of age and older) with NDD- CKD or PDD-CKD who are on erythropoietin therapy for iron maintenance treatment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Hypotension 5.3 Iron Overload 6 ADVERSE REACTIONS 6.1 Adverse Reactions in Clinical Trials 6.2 Adverse Reactions from Post-Marketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 1 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 1 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) 14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) 14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) 14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) 14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) 14.6 Study F: Iron Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How supplied 16.2 Stability and Storage 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. 1

5 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE is indicated for the treatment of iron deficiency anemia in patients with chronic kidney disease (CKD). 2 DOSAGE AND ADMINISTRATION must only be administered intravenously either by slow injection or by infusion. The dosage of is expressed in mg of elemental iron. Each ml contains 2 mg of elemental iron. 2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) Administer 1 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 1 mg diluted in a maximum of 1 ml of.9 NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. should be administered early during the dialysis session. The usual total treatment course of is 1 mg. treatment may be repeated if iron deficiency reoccurs. Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Administer 2 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 2 mg in a maximum of 1 ml of.9 NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 5 mg of, diluted in a maximum of 25 ml of.9 NaCl, over a period of 3.5 to 4 hours on day 1 and day 14. treatment may be repeated if iron deficiency reoccurs. 2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) Administer in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 3 mg over 1.5 hours 14 days apart followed by one 4 mg infusion over 2.5 hours 14 days later. Dilute in a maximum of 25 ml of.9 NaCl. treatment may be repeated if iron deficiency reoccurs. 2.4 Pediatric Patients (2 years of age and older) with HDD-CKD for iron maintenance treatment The dosing for iron replacement treatment in pediatric patients with HDD-CKD has not been established. For iron maintenance treatment: Administer at a dose of.5 mg/kg, not to exceed 1 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 ml of.9 NaCl and administered over 5 to 6 minutes. treatment may be repeated if necessary. 2.5 Pediatric Patients (2 years of age and older) with NDD-CKD or PDD-CKD who are on erythropoietin therapy for iron maintenance treatment The dosing for iron replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established. 2

6 For iron maintenance treatment: Administer at a dose of.5 mg/kg, not to exceed 1 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 ml of.9 NaCl and administered over 5 to 6 minutes. treatment may be repeated if necessary. 3 DOSAGE FORMS AND STRENGTHS 1 ml single-use vial / 2 mg elemental iron (2 mg/ml) 5 ml single-use vial / 1 mg elemental iron (2 mg/ml) 2.5 ml single-use vial / 5 mg elemental iron (2 mg/ml) 4 CONTRAINDICATIONS Known hypersensitivity to 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been lifethreatening and fatal, have been reported in patients receiving. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop immediately. Monitor patients for signs and symptoms of hypersensitivity during and after administration for at least 3 minutes and until clinically stable following completion of the infusion. Only administer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous iron preparations occur within 3 minutes of the completion of the infusion [see Adverse Reactions (6.1 and 6.2)]. 5.2 Hypotension may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of. Hypotension following administration of may be related to the rate of administration and/or total dose administered [See Dosage and Administration (2), Warnings and Precautions (5.1), and Adverse Reactions (6.2)]. 5.3 Iron Overload Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer to patients with evidence of iron overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of iron sucrose; do not perform serum iron measurements for at least 48 hours after intravenous dosing [See Dosage and Administration (2) and Overdosage (1)]. 3

7 6 ADVERSE REACTIONS The following serious adverse reactions associated with are described in other sections [See Warnings and Precautions (5.1, 5.2 and 5.3)]. 6.1 Adverse Reactions in Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice. Adverse Reactions in Adult Patients with CKD The frequency of adverse reactions associated with the use of has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by 2 of treated patients in the six clinical trials for which the rate for exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 1 mg doses at 1 consecutive dialysis sessions until a cumulative dose of 1 mg was administered. Patients with NDD-CKD received either 5 doses of 2 mg over 2 weeks or 2 doses of 5 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 3 mg followed by a dose of 4 mg over a period of 4 weeks. Table 1. Treatment-Emergent Adverse Reactions Reported in 2 of Study Populations and for which the Rate for Exceeds the Rate for Comparator Adverse Reactions (Preferred Term) HDD-CKD NDD-CKD PDD-CKD (N=231) (N=139) Oral Iron (N=139) (N=75) EPO* Only (N=46) Subjects with any adverse reaction Ear and Labyrinth Disorders Ear Pain.7 Eye Disorders Conjunctivitis Gastrointestinal Disorders Abdominal pain Diarrhea Dysgeusia Nausea Vomiting General Disorders and Administration Site Conditions Asthenia Chest pain Feeling abnormal Infusion site pain or burning Injection site extravasation Peripheral edema Pyrexia Infections and Infestations Nasopharyngitis, Sinusitis, Upper

8 Adverse Reactions (Preferred Term) HDD-CKD NDD-CKD PDD-CKD (N=231) (N=139) Oral Iron (N=139) (N=75) EPO* Only (N=46) respiratory tract infections, Pharyngitis Injury, Poisoning and Procedural Complications Graft complication Metabolism and Nutrition Disorders Fluid overload Gout Hyperglycemia Hypoglycemia Musculoskeletal and Connective Tissue Disorders Arthralgia Back pain Muscle cramp Myalgia Pain in extremity Nervous System Disorders Dizziness Headache Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Nasal congestion Skin and Subcutaneous Tissue Disorders Pruritus Vascular Disorders Hypertension Hypotension * EPO=Erythropoietin One hundred thirty (11) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous iron therapy and were reported to be intolerant (defined as precluding further use of that iron product). When these patients were treated with there were no occurrences of adverse reactions that precluded further use of [See Warning and Precautions (5)]. Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older) In a randomized, open-label, dose-ranging trial for iron maintenance treatment with in pediatric patients with CKD on stable erythropoietin therapy [see Clinical Studies (14.6)], at least one treatment-emergent adverse reaction was experienced by 57 (27/47) of the patients receiving.5 mg/kg, 53 (25/47) of the patients receiving 1. mg/kg, and 55 (26/47) of the patients receiving 2. mg/kg

9 A total of 5 (11) subjects in the.5 mg/kg group, 1 (21) patients in the 1. mg/kg group, and 1 (21) patients in the 2. mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2 of patients) in all patients were headache (6), respiratory tract viral infection (4), peritonitis (4), vomiting (4), pyrexia (4), dizziness (4), cough (4), renal transplant (4), nausea (3), arteriovenous fistula thrombosis (2), hypotension (2), and hypertension (2.1). 6.2 Adverse Reactions from Post-Marketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In the post-marketing safety studies in 1,51 treated patients with HDD-CKD, the adverse reactions reported by > 1 were: cardiac failure congestive, sepsis and dysgeusia. The following adverse reactions have been identified during post-approval use of. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, lightheadedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia. Symptoms associated with total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 3 minutes after the administration of injection. Reactions have occurred following the first dose or subsequent doses of. Symptoms may respond to IV fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms. Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation. 7 DRUG INTERACTIONS Drug interactions involving have not been studied. However, may reduce the absorption of concomitantly administered oral iron preparations. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, iron sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental iron (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to iron sucrose. Because animal reproductive studies are not always predictive of human response, 6

10 should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers It is not known whether iron sucrose is excreted in human milk. Iron sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of for iron replacement treatment in pediatric patients with dialysisdependent or non-dialysis-dependent CKD have not been established. Safety and effectiveness of for iron maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. at doses of.5 mg/kg, 1. mg/kg, and 2. mg/kg was administered. All three doses maintained hemoglobin between 1.5 g/dl and 14. g/dl in about 5 of subjects over the 12- week treatment period with stable EPO dosing. [See Clinical Studies (14.6)] has not been studied in patients younger than 2 years of age. In a country where is available for use in children, at a single site, five premature infants (weight less than 1,25 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received, several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to or any other drugs could be established. 8.5 Geriatric Use Clinical studies of did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,51 patients in two postmarketing safety studies of, 4 were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 1 OVERDOSAGE No data are available regarding overdosage of in humans. Excessive dosages of may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. Do not administer to patients with iron overload. [See Contraindications (4)] Toxicities in single-dose studies in mice and rats, at intravenous iron sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality. 7

11 11 DESCRIPTION (iron sucrose injection, USP), an iron replacement product, is a brown, sterile, aqueous, complex of polynuclear iron (III)-hydroxide in sucrose for intravenous use. Iron sucrose injection has a molecular weight of approximately 34, to 6, daltons and a proposed structural formula: [Na 2 Fe 5 O 8 (OH) 3(H 2 O)] n m(c 12 H 22 O 11 ) where: n is the degree of iron polymerization and m is the number of sucrose molecules associated with the iron (III)-hydroxide. Each ml contains 2 mg elemental iron as iron sucrose in water for injection. is available in 1 ml single-use vials (2 mg elemental iron per 1 ml), 5 ml single-use vials (1 mg elemental iron per 5 ml), and 2.5 ml single-use vials (5 mg elemental iron per 2.5 ml). The drug product contains approximately 3 sucrose w/v (3 mg/ml) and has a ph of 1.5 to The product contains no preservatives. The osmolarity of the injection is 1,25 mosmol/l. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action is an aqueous complex of poly-nuclear iron (III)-hydroxide in sucrose. Following intravenous administration, is dissociated into iron and sucrose and the iron is transported as a complex with transferrin to target cells including erythroid precursor cells. The iron in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells. 1 Pharmacodynamics Following intravenous administration, is dissociated into iron and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with iron sucrose containing 1 mg of iron, three times weekly for three weeks, significant increases in serum iron and serum ferritin and significant decreases in total iron binding capacity occurred four weeks from the initiation of iron sucrose treatment Pharmacokinetics In healthy adults administered intravenous doses of, its iron component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The iron component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating containing 1 mg of iron labeled with 52 Fe/ 59 Fe in patients with iron deficiency showed that a significant amount of the administered iron distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible iron trapping compartment. Following intravenous administration of, iron sucrose is dissociated into iron and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of containing 1,51 mg of sucrose and 1 mg of iron in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3 of the sucrose was eliminated in urine in 4 h and 75.4 in 24 h. Some iron was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single 8

12 intravenous dose of iron sucrose containing 5 to 7 mg of iron in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 6), approximately 5 of the iron was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of have not been studied. Pharmacokinetics in Pediatric Patients In a single-dose PK study of, patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of at 7 mg/kg (maximum 2 mg) administered over 5 minutes. Following single dose, the half-life of total serum iron was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 3135 hr μg/dl, respectively, which were and 1.67-fold higher than dose adjusted adult Cmax and AUC values. is not dialyzable through CA21 (Baxter) High Efficiency or Fresenius F8A High Flux dialysis membranes. In in vitro studies, the amount of iron sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million). 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with iron sucrose. Iron sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Iron sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay. Iron sucrose at intravenous doses up to 15 mg/kg/day of elemental iron (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats. 14 CLINICAL STUDIES Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD CKD) Study A was a multicenter, open-label, historically-controlled study in 11 patients with HDD-CKD (77 patients with treatment and 24 in the historical control group) with iron deficiency anemia. Eligibility criteria for treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8. and 11. g/dl, transferrin saturation < 2, and serum ferritin < 3 ng/ml. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57) were male and 33 (43) were female. 1 mg was administered at 1 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with, who were off intravenous iron for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 8 9

13 years. Patient age and serum ferritin level were similar between treatment and historical control patients. Patients in the treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2. Table 2. Changes from Baseline in Hemoglobin and Hematocrit End of treatment 2 week follow-up 5 week follow-up Efficacy parameters (n=69 Historical Control (n=73) Historical Control (n=71) Historical Control (n=15) (n=18) (n=18) Hemoglobin (g/dl) 1. ±.12**. ± ±.14** -.6 ± ±.17* -.1 ±.23 Hematocrit () 3.1 ±.37** -.3 ± ±.44** -1.2 ± ±.54.2 ±.86 **p <.1 and *p <.5 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates. Serum ferritin increased at endpoint of study from baseline in the -treated population (165.3 ± 24.2 ng/ml) compared to the historical control population (-27.6 ± 9.5 ng/ml). Transferrin saturation also increased at endpoint of study from baseline in the -treated population (8.8 ± 1.6) compared to this historical control population (-5.1 ± 4.3) Study B: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) Study B was a multicenter, open label study of in 23 patients with iron deficiency and HDD- CKD who had been discontinued from iron dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 1 (44) were male and 13 (56) were female. All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ±.2 g/dl), hematocrit (3.6 ±.6), serum ferritin (266.3 ± 3.3 ng/ml) and transferrin saturation (8.7 ± 2.) were observed from baseline to end of treatment Study C: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin 1 g/dl, a serum transferrin saturation 2, and a serum ferritin 2 ng/ml, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 7 years. Of 13 patients evaluated for efficacy in this study, 68 (52) were male and 62 (48) were female. Forty-eight percent of the patients had previously been treated with oral iron. Exclusion criteria were similar to those in studies A and B. was administered in doses of 1 mg during sequential dialysis sessions until a predetermined (calculated) total dose of iron was administered. A 5 mg dose (2.5 ml) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (2) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study. The modified intention-to-treat (mitt) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dl), hematocrit (5), serum ferritin (434.6 ng/ml), and serum transferrin saturation (14) were observed at week 2 of the observation period and these values remained 1

14 increased at week 4 of the observation period Study D: Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral iron versus in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of 11. g/dl, transferrin saturation 25, ferritin 3 ng/ml were randomized to receive oral iron (325 mg ferrous sulfate three times daily for 56 days); or (either 2 mg over 2 to 5 minutes 5 times within 14 days or two 5 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral iron group. A statistically significantly greater proportion of subjects (35/79; 44.3) compared to oral iron subjects (23/82; 28) had an increase in hemoglobin 1 g/dl at anytime during the study (p =.3) Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and IV iron to patients with PDD-CKD receiving an erythropoietin alone without iron supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of 11.5 g/dl, TSAT 25, ferritin 5 ng/ml were randomized to receive either no iron or (3 mg in 25 ml.9 NaCl over 1.5 hours on Day 1 and 15 and 4 mg in 25 ml.9 NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the / erythropoietin group was 51.9 years (range 21 to 81 years) vs years (range 23 to 77 years) for 46 patients in the erythropoietin alone group. Patients in the / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dl), compared to subjects who received erythropoietin alone (.6 g/dl) (p <.1). A greater proportion of subjects treated with / erythropoietin (59.1 ) had an increase in hemoglobin of 1 g/dl at any time during the study compared to the subjects who received erythropoietin only (33.3) Study F: Iron Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease Study F was a randomized, open-label, dose-ranging study for iron maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of (.5 mg/kg, 1. mg/kg or 2. mg/kg). The mean age was 13 years (range 2 to 2 years). Over 7 of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 6 of patients underwent hemodialysis and 25 underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dl, the mean TSAT was 33 and the mean ferritin was 3 ng/ml. Patients with HDD-CKD received once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 1.5 g/dl and 14. g/dl during the 12-week treatment period was 58.7, 46.7, and 45. in the.5 mg/kg, 1. mg/kg, and 2. mg/kg groups, respectively. A dose-response relationship was not demonstrated. 11

15 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How supplied is supplied sterile in 1 ml, 5 ml, and 2.5 ml single-use vials. Each 1 ml vial contains 2 mg elemental iron, each 5 ml vial contains 1 mg elemental iron, and each 2.5 ml vial contains 5 mg elemental iron (2 mg/ml). NDC mg/1 ml Single-Use Vial Packages of 5 NDC mg/1 ml Single-Use Vial Packages of 1 NDC mg/5 ml Single-Use Vial Individually Boxed NDC mg/5 ml Single-Use Vial Packages of 1 NDC mg/5 ml Single-Use Vial Packages of 25 NDC mg/2.5 ml Single-Use Vial Packages of 1 NDC mg/2.5 ml Single-Use Vial Packages of Stability and storage Contains no preservatives. Store in original carton at 2 C to 25 C (68 F to 77 F); excursions permitted to 15 to 3 C (59 to 86 F). [See USP Controlled Room Temperature]. Do not freeze. Syringe Stability:, when diluted with.9 NaCl at concentrations ranging from 2 mg to 1 mg of elemental iron per ml, or undiluted (2 mg elemental iron per ml) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25 C ± 2 C) and under refrigeration (4 C ± 2 C). IV Admixture Stability:, when added to IV infusion bags (PVC or non-pvc) containing.9 NaCl at concentrations ranging from 1 mg to 2 mg of elemental iron per ml, has been found to be physically and chemically stable for 7 days at controlled room temperature (25 C ± 2 C). Do not dilute to concentrations below 1 mg/ml. Do not mix with other medications or add to parenteral nutrition solutions for intravenous infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion. 17 PATIENT COUNSELING INFORMATION Prior to administration: Question patients regarding any prior history of reactions to parenteral iron products Advise patients of the risks associated with Advise patients to report any symptoms of hypersensitivity that may develop during and following administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)] 12

16 AMERICAN REGENT, INC. SHIRLEY, NY IN234 MG #15727 is manufactured under license from Vifor (International) Inc., Switzerland. 13